Organo-tin compounds having anti-tumour activity and anti-tumour compositions

ABSTRACT

The invention relates to anti-tumor compositions containing as an active ingredient one or more compounds of the formula 
     
         Ar.sub.3 Sn--O--C(O)--C.sub.6 H.sub.2 XYZ 
    
     wherein X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl. A number of these compounds are novel compounds.

This invention relates to novel organo-tin compounds having anti-tumouractivity and to anti-tumour compositions.

In addition to platinum compounds, such as cis-platin, cis-(NH₃)₂ Cl₂Pt, also organo-tin compounds are known anti-tumour drugs. An article byW. D. Honnick and J. J. Zuckermann, Inorg. Chem. 18, 1979, 1437-1443,"The Synthetis of Tin (IV) -Oxygen and Sulfur Heterocycles and theirtransformation to Tin (II) Analogues" describes a number of diorgano-tincompounds having anti-tumour activities, for instance ##STR1## (Adi-organo-tin compound is defined herein as a tin compound wherein twoorganic groups are bound directly to a Sn atom via carbon atoms).

In an article by V. L. Narayanan in "Structure-Activity Relationships ofAnti-Tumor Agents", ed. D. N. Reinhoudt, T. A. Connors, H. M. Pinedo andK. W. van de Poll, Martinus Nijhoff, 1983, p. 16-33, it is reported thatof 129 di-organo-tin compounds tested against P388 leukemia, 48% werefound active, whereas of 132 tri-organo-tin compounds only 9% were foundactive.

The present invention provides anti-tumour compositions, containing asan active ingredient one or more compounds of the formula:

    Ar.sub.3 Sn--O--C(O)--C.sub.6 H.sub.2 XYZ

wherein Ar is a substituted or unsubstituted phenyl group; X and Y areeach H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy,sulphonic acid or alkyl; and pharmaceutically acceptable excipient.

Molloy et al, J. Chem. Soc. Dalton Trans. (1988), 1259-1266, disclosecompounds of the formula

    (C.sub.6 H.sub.5).sub.3 Sn OC(O)C.sub.6 H.sub.5-n X.sub.n

wherein X=2-NH₂, 2-CH₃, 2-OCH₃, 2-F, -3F, -4F, 2-Cl, 3-Cl, 4-Cl, 2-Br,2-I (n=l) and 2,5-Cl₂, 3,4-Cl₂, 3,5-Cl₂, 2,4-Cl₂ (n=2). This articledoes not mention any pharmacological activity for these and relatedcompounds.

EP-A-119419 discloses the compound (C₆ H₅)₃ Sn--O--C(O)--C₆ H₅ OCOCH₃wherein the acetyl group is at the 2-position as a biocidal compound; apharmacological activity is not mentioned. U.S. Pat. No. 4,043,949concerns the use of triphenyltin-3-amino-2,5-dichlorobenzoate and otherorganotin-compounds as catalysts for the preparation of polyurethanefoams. Again, no pharmacological activity is mentioned.

Preferably, the alkyl group is isopropyl. The preset compounds can beprepared by reacting triphenyltin hydroxide with XYZC₆ H₂ COOH atelevated temperature.

PREPARATION

In all preparations, 2 g (5.4 mmol) of triphenyltin hydroxide was addedto a solution of 5.4 mmol XYZC₆ H₂ COOH in a mixture of 150 ml oftoluene and 50 ml of ethanol. This mixture is heated at reflux for 6hours; first the ternary azeotrope water/toluene/ethanol is distilledoff using a Dean-Stark funnel, followed by half of the reining solvent.The obtained solution is evaporated under vacuum. An oily compound isobtained; this material is crystallized from ethanol or from CH₂ Cl₂/petroleum ether.

The following compounds were prepared:

Triphenyltin ortho-methoxybenzoate, Compound 1

recrystallized from ethanol; m.p.: 102°-103° C.; yield: 68%; Rf onPolygram^(R) SIL G/UV₂₅₄ TLC plates from Macherey-Nagel+CO, elution withcyclohexane/dioxane 1/1:0.80; Mossbauer parameters (in mm/s: quadrupolesplitting QS:2.33, isomer shift IS: 1.22, band widths Γ₁ & Γ₂ : 0.92 &0.90; ¹ H NMR (CDCl₃) parameters (proton number: multiplicity, chemicalshift in ppm [coupling constants in Hz]: H-3: d, 6.94 [8]; H-4: dd, 6.95[7, 7]; H-5: hidden under the signals of meta and para protons; H-6: dd,7.98 [8, 2]; ortho-H: m: 7.78-7.82; meta- & para-H: m: 7.39-7.46; CH₃ O:s, 3.88.

Triphenyltin para-fluorbenzoate, Compound 2

recrystallized from ethanol; m.p.: 86°-87° C.; yield: 24%; Rf onPolygram^(R) SIL G/UV₂₅₄ TLC plates, elution with petroleum ether/aceticacid 6/1:0.51; Mossbauer parameters (in mm/s): QS:2.54, IS: 1.27, Γ₁ &Γ₂ : 0.85 & 0.86; ¹ H NMR (CDCl₃) parameters: H-2 & H-6: dd, 8.14 [9,6]; H-3 & H-5: dd, 7.05 [9, 9]; ortho-H: m: 7.76-7.81; meta- & para-H:m:7.45-7.51.

Triphenyltin 3,5-difluorobenzoate, Compound 3

recrystallized from ethanol; m.p.: 121°-122° C; yield: 30%; Rf onPolygram^(R) SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane1/1:0.53; Mossbauer parameters (in mm/s): QS:2.61, IS: 1.26, Γ₁ & Γ₂ :0.90 & 0.89; ¹ H NMR (CDCl₃) parameters: H-2 & H-6: dd, 7.62 [8, 2];H-4: tt, 6.94 [9, 2]; ortho-H: m: 7.76-7.82; meta- & para-H: m:7.45-7.51.

Triphenyltin acetylsalicylate, Compound 4

recrystallized from CH₂ Cl₂ /petroleum ether; m.p.: 110°-111° C.; yield:85%; Rf on Polygram^(R) SIL G/UV₂₅₄ TLC plates, elution withcyclohexane/dioxane 1/1: 0.85; Mossbauer parameters (in mm/s): QS: 2.54,IS: 1.27, Γ₁ & Γ₂ : 0.86 & 0.89; ¹ H NMR (CDCl₃) parameters: CH₃ :s:2.04; H-3: dd: 7.04 [8,1]; H-4: ddd: 7.23 [8, 8, 1]; H-6: dd: 8.11[8,2]; ortho-H: m: 7.64-7.90 [³ J(Sn--H)=60]; H-5, meta- & para-H:m:7.35-7.50.

Triphenyltin 5-chlorosalicylate, Compound 5

recrystallized from CH₂ Cl₂ /petroleum ether; m.p.: 122°-123° C.; yield:75%; Rf on Polygram^(R) SIL G/UV₂₅₄ TLC plates, elution withcyclohexane/dioxane 1/1: 0.76; Mossbauer parameters (in mm/s): QS: 2.79,IS: 1.32, Γ₁ & Γ₂ : 0.90 & 0.89, ¹ H NMR (CDCl₃) parameters: H-3: d:6.88 [9]; H-6: d: 7.94 [2]; ortho-H: m: 7.65-7.90 [³ J(Sn--H)=64]; H-4meta- & para-H: m: 7.45-7.53; OH: bs: 11.06.

Triphenyltin 5-aminosalicylate, Compound 6

recrystallized from CH₂ Cl₂ /petroleum ether; m.p.: 145°-146° C.; yield:78%; Rf on Polygram^(R) SIL G/UV₂₅₄ TLC plates, elution withcyclohexane/dioxane 1/1: 0.73; Mossbauer parameters (in mm/s): QS: 3.10,IS: 1.30, Γ¹ & Γ₂ : 0.90 & 0.89; ¹ H NMR (CDCl₃) parameters: H-3 & H-4:AB part of an ABX system with √_(A) =6.75, √_(B) 6.79, J_(AB) =9, J_(AX)=nv and J_(BX) =2; H-6: d:7.292 [2]; ortho-H:m:7.64-7.90 [³J(Sn--H)=54];meta- & para-H: m:7.40-7.50; NH₂ : m: 2.71-3.42; ¹³ C NMR(CDCl₃): ipso-C: 137.7 [¹ J(Sn--C)=630]; ortho-C: 136.7 [² J(Sn--C)=47];meta- C: 128.9 [³ J(Sn--C)=64]; para-C: 130.3; C-1: 113.1;C- 2: 154.8;C-3: 116.5; C-4: 124.0; C-5: 137.9; C-6: 117.6; CO: 174.8; ¹¹⁹ Sn NMR(CDCl₃): -116.1.

Triphenyltin 5-methoxysalicylate, Compound 7

recrystallized from CH₂ Cl₂ /petroleum ether; m.p.: 137°-138° C.; yield:72% Rf on Polygram^(R) SIL G/UV₂₅₄ TLC plates, elution withcyclohexane/dioxane 1/1:0.97; Mossbauer parameters (in mm/s): QS: 2.75,IS: 1.28 Γ₁ & Γ₂ : 0.91 & 0.90; ¹ H NMR (CDCl₃) parameters: CH₃ O: s:3.74; H-3: d: 6.864 [9]; H-4: dd: 7.024 [9.3]; ortho-H: m: 7.65-7.91 [³J(Sn--H) s 63]; H-6, meta- & para-H: m: 7.42-7.53; OH: bs: 4.5; ¹³ C NMR(CDCl₃): CH₃ O: 55.8; ipso-C: 137.9 [¹ J(Sn--C)=632]; ortho-C: 136.7 [²J(Sn--C)=47]; meta-C: 128.9 [³ J(Sn--C)=62]; para-C: 130.3; C-1: 114.0;C-2: 156.0; C-3: 118.0; C-4: 123.5; C-5: 151.8; C-6: 113.1; CO: 174.7;¹¹⁹ Sn NMR (CDCl₃): -97.6

Triphenyltin 5-hydroxysulfonylsalicylate, Compound 8

recrystallized from ethanol; m.p.: >350° C.; yield: 76%; Rf onPolygram^(R) SIL G/UV₂₅₄ TLC plates, elution with ethanol: 0.88; ¹ H NMR(DMSO-d₆) parameters: H-3: d: 6.818 (8); H-6: d: 8.105 [2]; ortho-H: d:7.771 (7) [³ J(Sn--H)=106]; H-4, meta- & para-H: m: 7.34-7.46; OH: bs:11.6, SO₃ H: 3.39-3.47; ¹³ C NMR (DMSO-d₆): ipso-C: 144.6; ortho-C:139.5; meta-C: 133.6; para-C: 134.3; C-1: 118.3; C-2: 165.8; C-3: 121.2;C-4: 137.5; C-5: 152.9; C-6: 132.7; CO: 179.3; ¹¹⁹ Sn NMR (DMSO-d₆):-276.7

Triphenyltin 3,5-di-isopropylsalicylate, Compound 9

recrystallized from ethanol; m.p.: 150°-151° C.; yield: 90%; Rf onPolygram^(R) SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane1/1: 0.78; m.p. >350° C.; yield 76%; Rf on Polygram^(R) SIL G/UV₂₅₄ TLCplates, elution with ethanol: 0.88; Mossbauer parameters (in mm/s): QS:2.56, IS: 1.28, Γ₁ & Γ₂ : 0.86 & 0.92; ¹ H NMR (CDCl₃) parameters:3-i-Pr: CH: sept: 3.344 [7]; CH₃ : sept: 1.231 [7]; 5-i-Pr: CH: sept:2.843 [7]; CH₃ : sept: 1.220 [7]; H-4: d: 7.236 [2]; H-6; d: 7.715 [2];ortho-H: m: 7.67 -7.91 [³ J(Sn--H)=59]; meta- & para-H: m: 7.40-7.49;OH: bs: 11.3; ¹³ C NMR (CDCl₃): 3-i-Pr; CH₃ : 24.1; CH: 33.4; 5-i-Pr:CH₃ : 22.4; CH: 26.9; ipso-C: 137.9 [¹ J(^(119/117) Sn-¹³ C)=648/618];ortho-C: 138.0 [² J(Sn--C)=48]; meta-C: 128.9 [³ J(Sn--C)=64]; para-C:130.3 [⁴ J(Sn--C)=13]; C-1: 112.1; C-2: 157.4; C-3: 136.2; C-4: 130.6;C-5: 138.6; C-6: 125.9; CO: 175.7; ¹¹⁹ Sn NMR (CDCl₃): -101.4

The above compounds were tested in vitro against the following humantumour cell lines:

MCF-7 mammary carcinoma (M cells)

WiDr colon tumour cells (W cells)

The tests were carried out according to the method of R. van Lambalgenand P. Lelieveld, the PIT method: an automated in vitro technique fordrug toxicity testing. Invest. New Drug 5, 161-165 (1987).

The ID₅₀ values in ng/ml for the above nine compounds and for two knowncompounds (compounds 10 and 11) were determined according to theabove-mentioned procedure. The ID₅₀ value is the amount which inhibits50% of the cell growth. The results are shown in the following Table.(C₆ H₅)₃ Sn--O--C(O)--C₆ H₂ XYZ

We claim:
 1. A compound of the formula

    Ar.sub.3 Sn--O--C(O)--C.sub.6 H.sub.2 XYZ

wherein Ar is phenyl; X and Y are each H, OH, halogen or alkyl; and Z ishalogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl, with theproviso that, when Z is alkoxy, acyloxy or alkyl, X and Y are not bothH; when Z is amino, X and Y are both not H or chloro; when Z is halogen,X and Y are not both H, and one of X and Y is not halogen; and when Z isalkyl, and one of X and Y is OH, the other of X and Y is not alkyl or H.2. A compound of the formula

    Ar.sub.3 Sn--O--C(O)--C.sub.6 H.sub.2 XYZ

wherein Ar is phenyl; X and Y are each H, halogen or alkyl; and Z ishalogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl, with theproviso that, when Z is alkoxy, acyloxy or alkyl, X and Y are not bothH; when Z is amino, X and Y are both not H or chloro; and when Z ishalogen, X and Y are not both H, and one of X and Y is not halogen.
 3. Amethod for the treatment of tumors comprising administering an effectiveamount of a compound of the formula

    Ar.sub.3 Sn--O--C(O)--C.sub.6 H.sub.2 XYZ

wherein Ar is phenyl; X and Y are each H, OH, halogen or alkyl; and Z isa halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl.
 4. A methodin accordance with claim 3, wherein said tumor is a mammary carcinoma ora colon tumor.
 5. In a method for the treatment of tumors which respondto treatment by organo-tin compounds comprising administering to apatient having such a tumor an effective amount of an organo-tincompound, the improvement wherein said organo-tin compound is a compoundof the formula

    Ar.sub.3 Sn--O--C(O)--C.sub.6 H.sub.2 XYZ

wherein Ar is phenyl; X and Y are each H, OH, halogen or alkyl; and Z isa halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl.